3-phenyl-4-acyloxycarbostyrils

ABSTRACT

A 3-PHENYL-4-ACYLOXYCARBOSTYRIL OF THE FORMULA:   2-(O=),3-PHENYL,4-(R-COO-)-1,2-DIHYDROQUINOLINE   WHEREIN R IS METHYL OR ETHOXY PREPARED BY TREATING 3PHENYL-4-HYDROCARBOXTYRIL WITH AN ACYLATING AGENT, WHICH IS USEFUL AS A MINOR TRAQUILIZER WITH LESS SIDE EFFECT AND LOW TOXICITY.

United States Patent 3,635,985 S-PHENYL-4-ACYLOXYCARBOSTYRILS Haruki Nishimura, Osaka-fu, and Yasutaka Nagai, Kyotofu, Japan, assiguors to Dainippon Pharmaceutical Co.,

Ltd., Higashi-ku, Osaka-shi, Osaka-fu, Japan N0 Drawing. Filed Jan. 27, 1970, Ser. No. 6,316 Claims priority, application Japan, Feb. 1, 1969, 44/7,498 Int. Cl. C07d 33/48 U.S. Cl. 260--287 R 3 Claims ABSTRACT OF THE DISCLOSURE A 3phenyl-4-acyloxycarbostyril of the formula:

wherein R is methyl or ethoxy prepared by treating 3- phenyl-4-hydrocarbostyril with an acylating agent, which is useful as a minor tranquilizer with less side eifect and low toxicity.

The present invention relates to 3-phenyl-4-acyloxycarbostyrils, and their production and use.

The said 3-phenyl-4-acyloxycarbostyrils are representable by the formula:

wherein R is methyl or ethoxy and include specifically 3- phenyl-4-acetoxycarbostyril and 3 phenyl-4-ethoxycarbonyloxycarbostyril.

The 3-phenyl-4-acyloxycarbostyrils [I] exert a taming effect in fighting mice. The test results on 3-phenyl-4- acetoxycarbostyril [I:R=CH and 3-phenyl-4-ethoxycarbonyloxycarbostyril [I:R=C H O] as well as some structurally related compounds and a commercially available minor tranquilizer, chlordiazepoxide, are shown below.

Test method Ten male mice of dd strain weighing 18 to 20 g. each were used and divided into 5 groups each consisting of a pair. Two mice were put on an electrical stimulator and a 200 ml. beaker was placed upside down over the mice. Electric stimulation was given at the intervals of 7 sec. (540 v., 3 ma.). The time until two mice began to fight was measured with a timer at various times after administration of the test compound and calculated in terms of the score of 1 to 9 respectively for 0 to 5 sec., 6 to 10 sec., 11 to 15 sec., 16 to 20 sec., 21 to 25 sec., 26 to 30 sec., 31 to 35 sec., 36 to 40 sec. and more than 40 sec. The dosage showing an average mark of 5 was taken as ED Results ED (mg/kg,

Test compound: per os) 3phenyl-4-acetoxycarbostyril 11.5 3-phenyl-4-ethoxycarbonyloxycarbostyril 10.5 3-phenyl-4-hydroxycarbostyril 100 3-phenyl-4-propionyloxycarbostyril 96.0 3-phenyl-4-phenacetyloxycarbostyril 100 3-phenyl-4-benzoyloxycarbostyril 100 3-phenyl-4-propoxycarbonyloxycarbostyril 96.0 3-phenyl-4-phenyloxycarbonyloxycarbostyril 100 1-ethyl-3-phenyl-4-acetoxycarbostyril 100 1-ethyl-3-phenyl-4-ethoxycarbonyloxycarbostyril 100 1-methyl-3-phenyl-4-hydroxycarbostyril 100 1-ethyl-3-phenyl-4-hydroxycarbostyril 100 chlordiazepoxide 18.0

From the above table, it is seen that 3-phenyl-4-acetoxycarbostyril and 3-penyl-4-ethoxycarbonyloxycarbostyril show a higher taming effect than chlordiazepoxide, whereas other structurally related compounds exhibit no material or only slight effect.

In addition, it is advantageous that the 3-phenyl-4- acyloxycarbostyrils [I] are less effective in muscle relaxation, which is considered as an unfavorable side action for the use of tanquilizers. For instance, when orally administered to mice, the ED values of 3-phenyl-4-acetoxycarbostyril and 3-phenyl-4-ethoxycarbonyloxycarbostyril are respectively 113.0 and 117.0 mg./kg. whereas the ED value of chlordiazepoxide is 45.3 mg./kg.

It is also advantageous that the toxicity of the 3-phenyl- 4-acyloxycarbostyrils [I] is extremely low. For instance, when the acute toxicity is determined by administering orally to mice, the LD values of 3-phenyl-4-acetoxycarbostyril and 3-phenyl-4-ethoxycarbonyloxycarbostyril are both more than 3,000 mg./kg., Whereas the LD value of chlordiazepoxide is 1,325 mg./kg.

Thus, the 3-phenyl-4-acyloxycarbostyrils [I] of the present invention are useful as minor tranquilizers with less side effect and low toxicity.

A clinical dosage of the 3-phenyl-4-acyloxycarbostyrils [I] depends on disease syndrome, body weight, age and administration mode, but it is generally in the range of 0.05 to 500 mg./day, preferably of 0.5 to 200 mg./day. They can be used in a unit dosage form as tablets or capsules for oral administration or optionally in combination with suitable adjuvants such as calcium carbonate, starch, lactose, talc, magnesium stearate, carboxymethyl cellulose and gum acacia. Further, they can be formulated into aqueous alcohol, glycol, oil solutions or oil-water emulsions for oral administration in the same manner as conventional medical substances are formulated.

According to the present invention, the 3-phenyllacyloxycarbostyril [I] is prepared by subjecting 3-phenyl- 4-hydroxycarbostyril of the formula:

H [II] to acylation. The acylation may be accomplished in one or two steps.

When carried out in one step, the 3-phenyl-4-hydroxycarbostyril [II] or its monoalkali metal salt (e.g. sodium salt, potassium salt) is treated with the reactive derivative of acetic acid or of carbonic acid ethyl ester in the presence or absence of a basic catalyst such as organic tertiary amine (e.g. pyridine, triethylamine, dimethylaniline) at a temperature from to 200 C., preferably from to 120 C. The reactive derivative may be acid halide, acid anhydride, nitrophenyl ester, thiocyanate, dithiocarbamate, trithiophosphonate or the like. If necessary, there may be employed as the reaction medium an inert organic solvent (e.g. benzene, toluene, dioxane, carbon tetrachloride).

When carried out in two steps, the 3-phenyl-4-hydroxycarbostyril [II] or its monoalkali metal salt (e.g. sodium salt, potassium salt) is first reacted with phosgene or nitro-substituted phenoxycarbonyl chloride (e.g. p-nitrophenoxycarbonyl chloride) in an inert organic solvent (e.g. dichloromethane, chloroform, dioxane, tetrahydrofuran) at a temperature from -10 to C. and the resultant 4-chlorocarbonyloxy compound is then reacted with ethanol in the presence of a basic substance such as alkali metal (e.g. sodium, potassium) or alkoxide of alkali metal (e.g. sodium ethoxide) at a temperature from 10 to 60 C. to obtain the 3-phenyl-4-acyloxycarbostyril [I1 Practical and presently preferred embodiments of th present invention are illustratively shown in the following examples.

EXAMPLE 1 Preparation of 3-phenyl-4-acetoxycarbostyril A mixture of 3-phenyl-4-hydroxycarbostyril (5 g.), acetic anhydride ml.) and pyridine (0.5 ml.) is heated on an oil bath at 120 to 140 C. for 2 hours. The reaction mixture is allowed to stand at room temperature overnight and concentrated under reduced pressure to remove acetic anhydride. The residue is recrystallized from methanol to give 3-phenyl-4-acetoxycarbostyril (4.2 g.) as crystals melting at 252 to 254 C.

EXAMPLE 2 Preparation of 3-phenyl-4-acetoxycarbostyril A mixture of 3-phenyl-4-hydroxycarbostyril (2 g.), pyridine (20 ml.) and acetyl chloride (2.5 g.) is heated on a water bath for 2 hours. The reaction mixture is allowed to stand at room temperature overnight and concentrated under reduced pressure to remove pyridine. The residue is recrystallized from methanol to give 3-phenyl- 4-acetoxycarb0styril (1.9 g.) as crystals melting at 252 to 254 C.

4 EXAMPLE 3 Preparation of 3-phenyl-4-ethoxycarbonyloxycarbostyril EXAMPLE 4 Materials: Grams 3 phenyl 4-ethoxycarbonyloxycarbostyril 5 Lactose Starch 9.5 Microcrystalline cellulose 20 Magnesium stearate 0.5

The above materials are mixed together, granulated and tableted in accordance with a conventional method to give 2,000 tablets, each weighing 50 mg.

What is claimed is:

1. A 3-phenyl-4-acyloxycarbostyril of the formula:

OCOR

wherein R is methyl or ethoxy.

2. 3-phenyl-4-acetoxycarbostyril. 3. 3-phenyl-4-ethoxycarbonyloxyearbostyril.

References Cited UNITED STATES PATENTS 3,542,785 11/1970 Carney 260-289 FOREIGN PATENTS 1,121,411 7/1968 Great Britain 260289 DONALD G. DAUS, Primary Examiner U.S. Cl. X.R. 

